文章：

髓性白血病发生中造血干细胞行为失调

Dysregulated haematopoietic stem cell behaviour in myeloid leukaemogenesis

原文发布日期：2020-05-15

DOI: 10.1038/s41568-020-0260-3

类型: Review Article

开放获取: 否

英文摘要：

Haematopoiesis is governed by haematopoietic stem cells (HSCs) that produce all lineages of blood and immune cells. The maintenance of blood homeostasis requires a dynamic response of HSCs to stress, and dysregulation of these adaptive–response mechanisms underlies the development of myeloid leukaemia. Leukaemogenesis often occurs in a stepwise manner, with genetic and epigenetic changes accumulating in pre-leukaemic HSCs prior to the emergence of leukaemic stem cells (LSCs) and the development of acute myeloid leukaemia. Clinical data have revealed the existence of age-related clonal haematopoiesis, or the asymptomatic clonal expansion of mutated blood cells in the elderly, and this phenomenon is connected to susceptibility to leukaemic transformation. Here we describe how selection for specific mutations that increase HSC competitive fitness, in conjunction with additional endogenous and environmental changes, drives leukaemic transformation. We review the ways in which LSCs take advantage of normal HSC properties to promote survival and expansion, thus underlying disease recurrence and resistance to conventional therapies, and we detail our current understanding of leukaemic ‘stemness’ regulation. Overall, we link the cellular and molecular mechanisms regulating HSC behaviour with the functional dysregulation of these mechanisms in myeloid leukaemia and discuss opportunities for targeting LSC-specific mechanisms for the prevention or cure of malignant diseases.

摘要翻译： 

造血作用由造血干细胞（HSC）主导，这些细胞产生所有谱系的血液和免疫细胞。维持血液稳态需要造血干细胞对压力作出动态响应，而这些适应性应答机制的失调是髓系白血病发生的基础。白血病发生通常呈渐进式发展，在白血病干细胞（LSC）出现和急性髓系白血病形成之前，遗传和表观遗传改变会在预白血病造血干细胞中逐步累积。临床数据揭示了年龄相关克隆性造血现象的存在，即老年个体中突变血细胞的无症状性克隆扩增，该现象与白血病转化的易感性相关。本文阐述了特定突变（增强HSC竞争适应性）如何与内源性及环境变化共同驱动白血病转化。我们综述了LSC利用正常HSC特性促进存活和扩增的机制，这构成了疾病复发和传统疗法耐药性的基础，并详细阐述了当前对白血病"干性"调控的理解。总体而言，我们将调控HSC行为的细胞分子机制与这些机制在髓系白血病中的功能失调相联系，并探讨了靶向LSC特异性机制以预防或治愈恶性疾病的潜在途径。

原文链接：

Dysregulated haematopoietic stem cell behaviour in myeloid leukaemogenesis